Poly(adenosine diphosphate ribose) polymerase-1 (PARP-1) is a protein implicated in DNA damage repair and is often overexpressed in ovarian/breast cancer. Several PARP-inhibitors (PARPi) have been deployed as chemotherapeutics such as Niraparib (Zejula, GSK) and Olaparib (Lynparza, AstraZeneca & Merck). Radiolabeling of PARPi offers a means to evaluate their target engagement in both the central and peripheral nervous systems. This can expedite the development of PARPi for treating cancers beyond ovarian/breast. [¹⁸F]Olaparib and [¹¹C]Niraparib were radiolabeled and their biodistribution were evaluated using total-body (TB) PET on the PENN PET Explorer. This study was conducted according to GSK and University of Pennsylvania’s policies on the Care, Welfare and Treatment of Animals and reviewed by the Institutional Animal Care and Use Committee at UPENN. Total-body distribution of [¹⁸F]Olaparib (n=4) and [¹¹C]Niraparib (n=5) were evaluated using a 90-minute PET scan in a healthy rhesus macaque model. Time-activity curves were generated for the central and peripheral nervous system. Venous blood was sampled prior to radiotracer injection and at 5-60 minutes post-injection. HPLC analysis was used to determine the parent fraction of each radiotracer. Linear fixed-effects model of response (AUC) of radiotracers, phase of crossover design, their two-way interaction along with baseline bodyweight, and dose per tissue were used for statistical analysis. [¹⁸F]Olaparib was isolated in > 95% RCP and with a molar activity of 8.2 ± 5.3 Ci/μmol at EOS with a radiochemical yield of 10%. [¹¹C]Niraparib was isolated in > 95% RCP with a molar activity was greater than 3.0 Ci/μmol at end of EOB with an average radiochemical yield of 5%. Both radiotracers demonstrated >90% parent fraction at 5 minutes post-injection. [¹⁸F]Olaparib maintains a higher parent fraction than [¹¹C]Niraparib after 60 minutes. Both radiotracers are metabolized via the hepatobiliary system. [¹¹C]Niraparib demonstrates significantly higher brain uptake and brain retention than [¹⁸F]Olaparib. [¹⁸F]Olaparib showed higher uptake in kidney (P-value=0.0591) and spleen (P-value=0.0115). This demonstrates that these tracers may be useful in guiding therapeutic development of CNS-specific PARPi. Total-body PET can distinguish between the differing routes of metabolism between the two PARP-inhibitors. Furthermore, these two PET tracers can be used to quantify target engagement of novel PARPi in vivo.

Nicole Goodwin

Merck & Co Inc

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